Untangling PANDAS & PANS: Conversations about Infection-Associated, Immune-Mediated Neuropsychiatric Disorders

S2 E11: Physician-Scientist Herb Lachman, MD, Talks about Recent Genetic Observations in PANS: DNA Damage Response Genes

• Susan Newman Manfull, PhD • Season 2 • Episode 11

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Dr Herb Lachman is a physician, behavioral geneticist, and professor at the Albert Einstein College of Medicine in New York City.  In his 44 years on the faculty, he has studied the molecular basis of schizophrenia, autism, and the broad category of neurodevelopmental disorders. More recently, a serendipitous inquiry about a major DNA Damage Response Gene, PPMD1, prompted Dr. Lachman to shift his focus to PANS (Pediatric Acute-Onset Neuropsychiatric Syndrome).

In the 11th episode of “Untangling PANDAS and PANS,” we discuss some basic information about genetics so that laypersons with an interest in this subject are able to assimilate his findings about DNA damage repair genes and their potentially significant role in neuropsychiatric conditions. These genes not only underscore the complexity of PANS and PANDAS but also point to the multifaceted interplay between genetics and the immune system at the intersection of the brain.

Genes are surely Dr. Lachman’s muse. He is quick to acknowledge that his sample sizes are small and biased, but they are nonetheless generating hypotheses to study more fully with larger data sets.

The simple question of why, given the ubiquity of Group A Strep, does only a small subset of patients develop PANDAS? Genetic mutations will very likely help to provide answers in the future.

To learn more about Dr. Herb Lachman's recent genetics findings on PANS, please refer to these two articles: 

https://karger.com/dne/article/doi/10.1159/000541908/914745/Ultrarare-Variants-in-DNA-Damage-Repair-Genes-in

https://pubmed.ncbi.nlm.nih.gov/35773312/

Disclaimer: The views and opinions expressed in this program are those of the speakers and do not necessarily reflect the views or positions of any entities they represent.

Credits: Music by Kingsley Durant from his "Convertible" album

To learn more about PANDAS and PANS and The Alex Manfull Fund, visit our website: TheAlexManfullFund.org

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Susan Manfull, PhD:

Untangling Pandas and Pans is a podcast about two little-known medical disorders characterized by the sudden and dramatic onset of symptoms such as obsessions and compulsions, vocal or motor tics and restricted eating behaviors, and a whole host of other symptoms following a strep or other bacterial or viral infection. I have the privilege of interviewing some of the top researchers and clinicians in this rapidly growing area, known by various names such as immune-mediated neuropsychiatric disorders, infection-associated neuroimmune disorders and autoimmune encephalitis, or simply PANDAS and PANS. My name is Dr Susan Manfull. I am a social psychologist, the executive director of the Alex Manfull Fund and the mother of Alex Manfull, who died at 26 years old due to PANDAS, a disorder my husband and I knew next to nothing about, certainly not that our daughter could die from it.

William Manfull:

This is episode 11 of Untangling Pandas and Pans, recorded February 19th 2025.

Susan Manfull, PhD:

Welcome everyone to the 11th episode of Untangling Pandas and Pans hosted by The Alex Manfull Fund. I am Susan Manfull and I am here with Dr Herb Lachman. He is a physician, a behavioral geneticist and a professor in several different departments in Albert Einstein College of Medicine in New York City. If you happen to find yourself on campus, you may find him in the Department of Psychiatry or Medicine, Genetics or Neuroscience, and although podcast listeners cannot see his young appearance in spirit, I can tell you unequivocally that they belie the length of his tenure at Albert Einstein. He's been on the faculty for 44 years. That's a lot of time to do research.

Susan Manfull, PhD:

He has long had an interest in the molecular basis of schizophrenia, as well as autism and neurodevelopment disorders, studying pluripotent stem cell technology, which is either generated from patients or by engineering control lines using CRISPR-Cas9 gene editing.

Susan Manfull, PhD:

I will let him elaborate on that, but his work currently now is devoted to and, thankfully for us, PANS, Pediatric Acute Onset Neuropsychiatric Syndrome, which is the broad category in which PANDAS falls.

Susan Manfull, PhD:

So I had the pleasure of meeting Herb through Rene Blanchard, the chair of EXPAND, the European Immuno-Neuropsychiatric Association, where Herb serves on the scientific and medical advisory board. He was working on a paper about ultra rare genetic variants in PANS. When I first met him, and he later presented that with Peter van der Spek at our second symposium here in Portsmouth, New Hampshire I was very grateful to make his acquaintance for many reasons, but not the least of which is his very patient tutorials that he has given me and I know many others about his genetic research. He keeps long hours. I met with him Sunday morning at seven o'clock in the morning because I think he genuinely and passionately loves his research and, as I alluded to above, he does generously give his time to others like me to help us understand what I feel is a very complicated subject. However, he does manage to find time to travel. He's an avid traveler and I believe that he is heading to someplace in Mexico soon, that's right.

Susan Manfull, PhD:

And when not in his lab, he may be out riding his bicycle. I asked him where he rides and he mentioned the rail trails near his house in upstate New York. When he's in the city, you might find him in Central Park or riding along the Hudson River. He did confess that he no longer rides in the 100 mile races through New York City. I have a feeling he could if he wanted to. Anyway, he's a very interesting man and I'm very grateful for the fact that he's here with us today.

Dr. Herb Lachman:

I'm impressed with myself. That was a great, great intro. Who is it? Who is this guy?

Susan Manfull, PhD:

All right, well, we have a lot to talk about. The uh, the title that we came up with is something to the effect of making sense of of recent genetic findings in PANS patients, and Dr. Lachman will be talking especially about DNA damage response genes. But before we get started on any of that, I'm always curious how researchers find their way to the particular area of research that they're in. So how did you get interested in the genetics of PANS?

Dr. Herb Lachman:

Well, it was really quite a set of coincidences. I was working on a condition. I am working on a condition called Janssen-DeVries syndrome, which is due to mutations in this gene called PPM1D, and that's a gene that's really important for repairing DNA, which I guess I'll talk about later on.

Dr. Herb Lachman:

And.

Dr. Herb Lachman:

I got interested in that because I have a cancer genetics background and the control of DNA repair is a critical cancer mechanism. So I was always interested in DNA repair and when I found out about Janssen-DeVries syndrome I got some money to start studying this problem by making stem cells from patients' blood. And those stem cells can be turned into neurons and the brain the immune cells called microglia and we studied the molecular basis of what effect PPO1D mutations have on neuronal and microglia function. So that was the background.

Susan Manfull, PhD:

Before we go on, just so the listeners know, could you just tell us how the manifests itself?

Dr. Herb Lachman:

So this is manifested by an intellectual disability and severe anxiety and gastrointestinal problems. They have very severely restricted eating, which is one of the pans of symptoms, and they generally don't have OCD. And they're very, very nice kids. They have a very nice disposition like kids with Williams syndrome. But every now and then some of these kids have very severe neuropsychiatric decompensation resembling pants. That's in a very small subgroup of patients. Most of the kids don't have that, but a few do when looking at the genetics of that. But that part came later on how prevalent is that disorder?

Dr. Herb Lachman:

well, just degrees is very rare. Uh, I think they're about a couple hundred case reports. So, uh, but it's under diagnosed because not everybody's getting dna sequencing done. Uh and um, you know, the prevalence will will go up as we do more sequencing. Right now there are, you know, a couple hundred cases in the Janssen-DeVries Foundation website.

Susan Manfull, PhD:

Okay, so you found yourself interested in that disorder because you were interested in the gene.

Dr. Herb Lachman:

Yes, because it's a DNA repair gene and I have a very strong cancer genetics background and that pathway is really critical for many, many cancers.

Susan Manfull, PhD:

Interesting. Okay, so there you were, studying that. How did you find your way over to PANS? Well, renee emailed me. Well, Rene emailed me. Renee knew a family that had two kids with PANS who had mutations in the PPM1D gene and they were found by Peter Peter Van Der Spek from the Netherlands. And she said what do we do next? And he said, well, find the world's expert on PPM1D and that's not me, that's somebody else. And if she had gone to that other person he would have dismissed the whole thing most likely.

Dr. Herb Lachman:

and I was open to hearing about the condition and she told me about PANS patients and how the families were suffering because diagnosis is not in the DSM-5.

Dr. Herb Lachman:

So it's largely dismissed by most of the psychiatric community. And I heard these stories, these terrible stories of what the families were going through, and I was really, really I hate to sound Pollyannic I was really moved by these stories and I felt that it was a social justice situation. Some of these families were having nightmarish connections, interactions with law enforcement, with the education system, and even if the parents were being dismissed, the parents know a lot about these conditions. They know much more than doctors do and when a lay person goes to a doctor armed with data that they don't know, the short reaction is to dismiss that and I thought that was really unprofessional and anti-intellectual. And I'm very open to hearing what parents and patients have to say and I'm very happy to admit that I don't know what's going on and I'll find out more about it when I explore the literature. So I found that attitude to be really, really dismissive and even if you don't believe it, you don't have to dismiss what the parents are telling you.

Susan Manfull, PhD:

Right, aren't you curious? Yeah, yeah.

Dr. Herb Lachman:

Right, yeah, absolutely, you have to be curious. It's a fascinating condition and even but even if it's not true, it is true, but even if it's not true, the parents need to have some respect. Now, 90% of the families, who, 90% of the parents who are dealing with PANS, who are learning about it, who are communicating with doctors and finding healthcare professionals and talking to each other, they're mothers. And so you have this situation Not only do we have a layman or layperson seeing a doctor, it's a woman seeing the doctor. So you have this patriarchal mentality which increases the dismissiveness even more. The doctors are more inclined to dismiss a woman than they are a man, although both sexes do get dismissed. But I felt that was really an injustice as well.

Dr. Herb Lachman:

And Peter had sequenced a few other families, a few few of the kids with pans, and he told me what those findings were. And immediately, uh, it became pretty clear that we were dealing with a very genetically heterogeneous condition, meaning that there were many, many different genes that could be involved. And that explains, or it explained to me, my novice state at that time. That was like four or five years ago. I knew nothing about immunology, nothing about neuroinflammatory disorders. I knew nothing except for my own field. But it became clear that the reason why there have been so many problems in proving the effectiveness of certain medications like antibiotics and IVIG and so on, is because of genetic heterogeneity. That one patient might respond very well because he or she has an underlying genetic matrix that is conducive to being responsive to these medications and others do not. They have different causes and different responses to treatment that could all have a genetic basis.

Dr. Herb Lachman:

And that makes it much more challenging to prove that certain medications work, but it explains why, at least theoretically, why you might have run into problems in proving a particular medication is effective. So that launched me into that and then I contacted a PANS clinician in the US who had been sequencing a lot of his patients, that's Dr Cifraletti, and we put together his cases and other cases that Peter had sequenced and a couple of cases that I sequenced and we came up with this story that was published a couple of years ago and the most important revelation in that study was that there were a couple of years ago and the most important revelation in that study was that there were a couple of genes that were involved in DNA repair. Ppmd was one of them and the other one was another gene that's involved in that reaction in that response.

Dr. Herb Lachman:

So my brain was focusing on on DNA repair, the first um conference that I attended, uh, with you in 2022 that story to tell and I asked her whether or not her daughter had had had genetic analysis done and she said yes. I said what was the gene? And she said ATM. And ATM is connected to PPO and D and the other DNA repair gene that we found in the first study. When I heard that, my head exploded. Wow so that's what, that's how, that's what that's meant to be the DNA repair story. That was your first, the first conference that I attended, you know, in New Hampshire back in 2022.

Susan Manfull, PhD:

Wow, I'm so glad that we played a small role at least in seven.

Dr. Herb Lachman:

I mean it was a big role For you to learn more. Well, you get people together and that's what happens. That's the whole point of having a conference, I agree. It worked really well. It worked very well for me.

Susan Manfull, PhD:

Yeah, I completely agree. So it was at first the PPM1D. The light bulbs went off.

Dr. Herb Lachman:

That was the initial little flicker.

Susan Manfull, PhD:

Yeah.

Dr. Herb Lachman:

And then ATM was the full blast furnace.

Susan Manfull, PhD:

All right, so we're going to get into talk about those things, but I thought maybe we should hear a little bit about how gene mutations are identified, so that when you go on to talk about this, we can follow you.

Dr. Herb Lachman:

Yeah, okay. So the first thing is, when we say we have a gene for an abnormality, for a condition, it's not the gene per se. Everybody has the same genes. It's a mutation in those genes that are affecting gene function. So if I say that the PPOMD gene is involved in Janssen-DeVries syndrome and a small subgroup of PANS, it's not the gene per se. It's a very unique mutation in that gene that's doing that so when we say genes we mean mutations in those genes.

Dr. Herb Lachman:

And the way we analyze genomes now is through something called next generation sequencing. Now the first human genome. The human genome is gigantic. It's got 6 billion DNA letters 6 billion compared to bacterial species or small microbes, viruses and bacteria, which contain a million or so. So the human genome is really gigantic and sequencing is a real challenge.

Dr. Herb Lachman:

And the first sequence, the first DNA sequence, was published in 1990 or so. That was the culmination of the Human Genome Project. It cost $10 billion for the bee for that first sequence and it took 10 years. The insurance company will not pay $10 billion for a DNA sequence that was carried out using the classic technique of DNA sequencing which was discovered by Fred Sanger back in the 1970s, which earned him a Nobel Prize. So that's a sequencing strength. It's really elegant. I'm not going to go into details. I mean it's only poetry to scientists, but it is a really beautiful technique. Next-generation sequencing used that technology, at least at the beginning, and really ramped it up to the point where you can sequence the entire human genome in a couple of weeks for a few thousand volts whoa so with next generation sequencing.

Dr. Herb Lachman:

We people have been sequencing tens of thousands, hundreds, hundreds of thousands of genomes and we get this gigantic database of dna variation across the human genome.

Susan Manfull, PhD:

So so when you order DNA, yeah. Well, what year did that begin where the price went down so much?

Dr. Herb Lachman:

That's been going down steadily over the past decade and the cost has been halved every couple of years for the last decade. Now, I would say that started back in about 2012 or so. Give or take a couple of years. For the last decade. Now you know it's. I would say that started back in about 2012 or so. Give or take a couple of years.

Dr. Herb Lachman:

Okay, and some very clever scientists figured out other ways to sequence dna rapidly that doesn't rely on the sanger technique. So there are many, many different techniques, but uh, that one, uh, they're all collectively called next-generation sequencing. The bottom line is that it's cheap and relatively easy to sequence the DNA. So when a kid comes to a doctor with, let's say, autism or some neurodevelopmental disorder, they get some basic DNA analysis done. They don't get the full treatment. They don't get the full, whole exome, what we call whole exome sequencing or whole genome sequencing. They usually get a panel.

Dr. Herb Lachman:

If a doctor writes down on a report this kid has autism, they'll analyze a panel of genes, only a fraction of the 25,000 or so genes in the genome. That's what insurance companies will pay for. Basically they use the same kind of technique, but they only analyze a small fragment of the possible genetic variations. It is really really hard to do that, to analyze the entire genome. It's very hard on my end to look at the mutation to say you know what's going on over here, is this relevant or not? So the companies to cut back costs? What's going on over here? Is this relevant or not? So the companies to cut back costs? They only analyze panels of genes.

Dr. Herb Lachman:

Generally, when we sequence it for research we do a much more extensive analysis and some companies will do it also. Patients pay out of pocket. Some insurance companies will pay for the more extensive genetic analysis but by and large most families will get back some kind of panel of genes relevant to the kid's disease. And unfortunately the genetics of PANS is complicated. It doesn't exist yet. It only exists in my two papers and in my brain. So the company is not saying well, we need to analyze her blackened jeans. It's not. It's not there yet. So that's why the typical panel analyses that are done are suboptimal. It's the best you can do right now. But it is suboptimal. It doesn't tell you the whole pan genetics story as I think it exists.

Susan Manfull, PhD:

Okay, so last, I forgot, I thought I would do this at the end. But since we're on this subject, if a parent does want to have some genetic testing maybe not the whole genome sequencing, but something that would be valuable in understanding the genetic picture of their child or the young adult of his or her James what would you recommend?

Dr. Herb Lachman:

Oh, that's really hard to say. I recommend the full analysis but you can't get that insurance to pay for that Right now. In the US, standard care of any kid who has either autism, a neurodevelopmental disorder or an immune deficiency they'll get the panel for immune deficiencies. If they have autism they'll get the autism panel and that's standard care plus separate analysis for the fragile X, which can only be analyzed using a separate technique, and they can have a chromosomal study also done to look for what we call copybearance. So it's a whole slew of different genetic studies but most kids will have a copy variation analysis study and a panel analysis and analysis for fragile X, which is the most common cause of autism and intellectual disability, and if the doctor is savvy enough they can argue for doing a more extensive analysis.

Susan Manfull, PhD:

Okay, so is there. Maybe I misunderstood. Is there a particular name for that panel?

Dr. Herb Lachman:

Well, it depends on the company that the doctors are familiar with.

Dr. Herb Lachman:

So if you go to Invitae or you know, they have their own different names for the panels and because the costs are coming down. Uh, it's much, much easier to get, uh, it's cheaper to get what we call exome sequencing done, which is an analysis of the genes that code for proteins about 25 000. Of those, the panels typically analyze 500,000, which is only a small fraction of the 25,000 that exist in the genome. But with costs coming down, it'll become very cost-effective to do a much more extensive analysis.

Susan Manfull, PhD:

And we can talk about this later, but of course you would need someone to read that panel, correct?

Dr. Herb Lachman:

Well, the companies analyze the data. So what they do is, if you write down on the patient summary what the kid has autism, learning problems, dyslexia, adhd they will analyze the genes that are known likely to be involved in those conditions. There are a thousand different autism genes that have been published, so they have a whole panel of genes that they known likely to be involved in those conditions. There are a thousand different autism genes that have been published, so they have a whole panel of genes that they can analyze. And what they do is they look for variants that are potentially pathogenic and they have different algorithms that are used to try and figure out what variants should be looked at. One of the major filters is to look for variants that are very, very rare. So in human genetics, in complex traits, which is all psychiatric disorders, you have common variants and rare variants, and the rare variants are the ones we go after because those are the ones that are more likely to have a strong effect on biology. So one of the first filters is they're only going to look at mutations where the frequency of the mutation is present in less than one in a thousand kids. So you'll miss the other ones. But it's very hard since, let's say, you have a mutation that's found in one in every hundred people. Well, that far exceeds the number of cases. So the significance of that clinically really can't be figured out from a single case. Those studies to look for common variants are really research studies. It's a whole different type of analysis but for patients, for the whole exome sequencing, the whole genome sequencing, the first filter is to only look for mutations that are present in less than one in a thousand cases. And then there are different algorithms that the companies use to determine the pathogenicity of those mutations and that's.

Dr. Herb Lachman:

You know, you can't test, you can't do biological tests on every variant to say, oh, this variant is doing X, y and Z. It's impossible, it's not possible to do that. So you have these computer algorithms to say, okay, this mutation exists and it looks like it's pathogenic or likely pathogenic or benign. So that's the next filter. It goes through all those and it'll report to the doctors who order the tests. You'll get a list of variants and it'll say either a variant of unknown significance, a VUS, it'll say pathogenic or likely pathogenic and it will not report benign variants, pathogenic or likely pathogenic, and it will not report benign variants as predicted by the different tools that are used to assess functionality. And again, this is a predicted functionality and not a true biological functionality. That can only be done in the lab and that cannot be done on all the variants that are found. A very small minority of variants are scrutinized on the biological level because it's too hard, too expensive.

Susan Manfull, PhD:

This is very complicated. So that's what you essentially did in that first paper with Dr Trifiletti and a whole slew of other people the identification of ultra-rare genetic variants in PANS using exome and whole genome sequencing the. You found two classes.

Dr. Herb Lachman:

That's right right.

Susan Manfull, PhD:

And one you labeled synaptic function and the other the immune system.

William Manfull:

Right.

Susan Manfull, PhD:

Can you elaborate a little bit on that?

Dr. Herb Lachman:

and then we can do the DNA repair we can get the DNA repair.

Dr. Herb Lachman:

So a lot of kids with PANS have underlying autism or neurodevelopmental problems and or immune deficiencies a very, very large fraction. And what we're finding in some of those genes may not be actually PANS genes per se or autism regression genes per se. They're genes that these kids happen to have and they have as one of the manifestations of the illness they have PANS. Some of the genes that we found likely are in that category. So the immune genes are the ones that affect the immune system. I mean, I can't go into.

Dr. Herb Lachman:

The immune system is like the second brain. It is amazingly complicated. The most important, the most complicated structure on the planet is the human brain and the second is the human immune system and of course both are involved in PANS, which makes it an ultra complicated disorder. And the immune system is just a thing of beauty, and again I'm going to go down this nerve track if you let me, so don't let me. It is a thing of great, great beauty and I wish people could appreciate how that's how it works. I'll say one thing about the immune system. We have the ability to produce tens of millions of different antibodies to pathogens that existed in the past, to pathogens that will come to us in the future. We have the ability to produce tens of millions of different antibodies.

Susan Manfull, PhD:

We only have 25,000 genes.

Dr. Herb Lachman:

How is that possible? What happens is that you have the, the the genes that make antibodies are modules and basically you have recombination occurring. You have these modules uh, being expressed randomly in in immune cells during development. Uh, that will tell this b cell, this immune cell, this antibody immune cell, this antibody-producing cell, you are only going to produce this antibody and that antibody is due to the fact that these modules got rearranged during development.

Dr. Herb Lachman:

So you might have a small set of modules, a handful of modules, but you have a near infinite number of possible combinations, and those combinations are totally random. So we're born with this repertoire of B cells, the antibody-producing cells that can respond to literally any foreign substance. So it's this modular format that allows us and other animals to make antibodies to everything, even though we only have a small number of genes. So that was a Nobel Prize in the 1970s. And the same thing is true for the other part of the immune system, the T cells, which have T cell receptors. That also, you can make tens of millions of different T cell receptors from a small handful of genes through this random recombination that occurs during development.

Susan Manfull, PhD:

So we have that situation Anyway yes, so that helps me understand when people say they simply haven't perhaps haven't identified the antibody for this particular disorder. I mean, if there's so many out there antibody for this particular disorder.

Dr. Herb Lachman:

I mean, if there's so many out there? Well, not exactly. So the antibodies that are produced are produced to respond to a pathogen, the autoantibodies that are produced autoimmune disorders are due to a during development. You have these cells that turn off, that knock out those T cells and B cells, those antibody-conducing cells and those T cells. It knocks out those that recognize self-antigens, the proteins that we have in our own bodies and in autoimmune disorders that process escapes. So you lose the ability to control the attack against your own body. So those antibodies and the reason why those antibodies are hard to find is not because of that process that I mentioned earlier, it's due to you know, it's very hard to find antibodies that are specific for a particular protein or antigen.

Dr. Herb Lachman:

So, it's a somewhat different way of looking at it. That's a tech issue Finding antibodies or not. Finding antibodies, which is very, very important in diagnosing these conditions, is due to how much autoantibody somebody is producing. How good are the tests. A whole slew of different factors go into why, or why not, you might find an antibody.

Susan Manfull, PhD:

Okay, interesting, all right. So you identified the two different classes of genes and your curiosity was piqued, especially, I think I'm gathering, from the DNA damage.

Dr. Herb Lachman:

Right right.

Susan Manfull, PhD:

So do you want to tell?

Dr. Herb Lachman:

us. Yeah, before I get to that, let me just mention one thing about the neuronal genes. A lot of the kids in the first study had underlying autism and it turns out that some of the genes that we found the first study had had underlying autism. And it turns out that some of the genes that we found really they're really autism genes, but those genes, for some reason, reasons we don't, we don't know yet those genes, uh that cause autism are. Those kids are more prone to having some kind of immune attack that leads to pans or regression in autism, attack that leads to PANS or regression in autism. One of them was SHANK3. Shank3 is a very commonly mutated gene in autism and patients with SHANK3 mutations, for many, many studies, are much more prone to a neuropsychiatric decompensation following infection or some non-infectious stressor, and I mean a physical stressor, not an emotional one. So some of those genes that cause autism are more prone to an acute breakdown mediated by immune cells, and Shank 3 is the best example of that. So what we found? There were kids with Shank 3 mutations that had autism, that also had autism, uh, that also had it and had pants okay, so so so dna repair dna repair right

Susan Manfull, PhD:

okay, so we had these two and I guess the reason I want to focus on on something like that. As you said at the very beginning, this is such a complex, heterogeneous kind of disorder that I think it would it behooves us to focus on one part now and then maybe you'll come back and talk about another class of genes that are-.

Dr. Herb Lachman:

Other classes now. Other classes, okay, more classes now.

Susan Manfull, PhD:

Other classes Okay.

Dr. Herb Lachman:

More than one? Yeah, more than one, okay. So, so my brain is tuned into DNA repair.

Dr. Herb Lachman:

Okay, I went to your conference I met the parent of a child who had an ATM mutation and then I started. Then I started to do my own sequencing and After the conference A lot of families were sending me their DNA reports, started to do my own sequencing and after the conference a lot of families were sending me their DNA reports and they, the doctors, really couldn't make any sense of it. So I was looking at the reports and I was sequencing my own, my own samples now and doing a much more extensive analysis of the other, of the genetics, than what the drug companies, what the genetics companies, were producing for the families. I was really diving deep into the genomes. I spent, I would say, every one of these genomes that I look at. It takes me roughly 10 to 20 hours to analyze them.

Susan Manfull, PhD:

Oh.

Dr. Herb Lachman:

Yeah, so I do it almost one by one because I'm all time. I can't just rely on computation. I need to see the genes and get a feel for it, and I only get a feel for it when I look at the list of genes and something hits in my brain. I do the bioinformatics too. I do the computations. You have to do that, but I need to feel the genes. So that's why it takes me a very long time and I dig deep into the potential functionality of these genes using tools that are not used yet by these genetic companies, and those tools help to inform whether or not these mutations that I'm finding are relevant. So it takes me a long time to look at this Again. I'm going to go down the nerd trail here.

Dr. Herb Lachman:

The most fun I have in life, one of the most fun things I do, is getting these DNA sequencing data and looking at the thousand genes that come back after we do our filtering and looking at them and trying to figure stuff out. And I drop everything. When I have a sequence on my computer, I drop everything to look at it, because to me it's fun. Believe it or not, it's really fun. So I really like doing that. That's why it takes me a long time. I really look at it and really try to get a feel for the genes that you can't get when you plug in the genes into some kind of database. I do that too. You have to do that.

Dr. Herb Lachman:

But I have to feel the genes.

Susan Manfull, PhD:

Feel the genes I have to feel.

Dr. Herb Lachman:

the genes Feel the genes I have to feel the genes. That's right.

Dr. Herb Lachman:

So, doing that, we ended up finding a bunch of other genes where we had pathogenic mutations or likely pathogenic mutations in other DNA repair genes, and that led to our second paper, second paper and that resulted in the identification of nine or 10 other genes that separated into two different DNA repair pathways. One of them clustered around the process that PPMD and ATM work at, which is the so-called P53 pathway, and the other one revolved around what's called the Fanconi anemia complex pathway. All DNA repair genes and I have, I would say, another dozen waiting in the wings.

Susan Manfull, PhD:

Another how many?

Dr. Herb Lachman:

Another dozen genes that I haven't published yet. So we have that second paper, we have these two families of DNA repair genes and one really important caveat in all this is that many of the mutations we find, you find them at very low frequencies in the population. They do exist and it's really important to do an analysis where you compare the number of cases you have that have these mutations with what's found in the general population and when we do that we give us some kind of significant number to satisfy the statisticians and the geneticists. Only the ATM gene comes back significant. The other ones don't, and the reason for that is that our sample size is too small.

Susan Manfull, PhD:

Okay, so the PPM1D, doesn't come back.

Dr. Herb Lachman:

significant no it does not, it is. It clearly is.

William Manfull:

This is why what I mean.

Dr. Herb Lachman:

I feel the genes. The significance value is great to have and it is important to have to convince other scientists, but for me I need to. There's no question that this is a DNA repair gene and there's no question that a small subgroup of patients with Janssen-DeVries syndrome have an acute neuropsychiatric decompensation. There's no question about that. But I don't have the actual numbers to prove that yet. That will require a very, very, very large and expensive study to accomplish.

Susan Manfull, PhD:

Which, of course, would be difficult with this population, since it's relatively small.

Dr. Herb Lachman:

Yeah, Well, PANS is not in DSM-5. So it's a clinical diagnosis. Those of us in the PANS community believe in it, but those who fund us may not.

Susan Manfull, PhD:

So you said that these genes occur in those who have cancer or some types of cancer?

Dr. Herb Lachman:

So the P53 pathway this goes back to. I was an early researcher on P53, it turns out P53 is the most commonly mutated gene in cancer by far. When you have a defect in DNA repair in a cell, that cell doesn't fix DNA breaks, which occur naturally as cells divide. And the more DNA breaks you have, the less able you are to repair those breaks, the more cancerous the cell becomes. The cell loses its control over growth and becomes cancerous. And p53 is the number one gene that is mutated in cancer. Now those mutations occur after fertilization. They occur in our bodies. They're called somatic mutations. They're mutations that occur by chance in our bodies as we age, as we expose ourselves to cancer-causing DNA breakage. So everybody alive has thousands of mutations that we've accumulated in ourselves randomly because of mistakes that happen when cells divide, when we go out into the sun too long, when we eat carcinogenic or smoke carcinogenic agents. Those agents increase the number of DNA mutations that occur.

Dr. Herb Lachman:

So DNA mutations occurring after fertilization, so-called somatic mutations, are the major pathway involved in cancer. Cells lose the capacity to control cell growth because of mutations in genes that regulate that process and regulate P53 DNA repair. That's one of the major cancer pathways. Now, these kids that we have with PANS, they're born with these mutations and those mutations. When they happen during development, when they happen at fertilization or from transmission from a parent, or de novo during ergo sperm formation, those mutations lead to neurodevelopmental problems. Some kids who have these germline mutations in those genes that cause autism or other neurodevelopmental problems end up having a higher risk for having cancer.

Susan Manfull, PhD:

Oh, interesting.

Dr. Herb Lachman:

And we don't know yet about the PPM1D in these kids with and we don't know whether the cancer risk has increased in those kids. There may be something different about being born with these mutations having that mutation existing at fertilization as opposed to having it as part of this stepwise conversion of a normal cell into a cancer cell when these mutations occur after development. Stepwise conversion of a normal cell into a cancer cell when these mutations occur after development. So there may be some differences there. We don't know yet.

Susan Manfull, PhD:

Maybe this is a silly question, but how do you know that the children were born with those genes?

Dr. Herb Lachman:

Well, because they have them in every cell in the body.

Susan Manfull, PhD:

Okay, okay.

Dr. Herb Lachman:

That's one. So in 95% of the kids have a de novo mutation, meaning that the parents don't have it and you can analyze parents, they don't have it, the kids have it and they have it in every cell. Some kids have mosaicism for that, so half the cells might have the mutation and half that don't. And that happens. That happens, uh uh. That mutation occurs after fertilization, but typically the normal mutations occur during egg or sperm formation and it leads to that mutation happening in every cell in the body. But if it happens after fertilization, in the first or second cell division after fertilization, then the kid becomes a mosaic for that mutation and every now and then the parent, who's relatively asymptomatic, will transmit one of these genes to their offspring.

Susan Manfull, PhD:

Okay, so you've discovered the DNA Right. Genes are culpable, perhaps. Right right In this disorder. So what else do we need to know about how this leads to the symptoms?

Dr. Herb Lachman:

Okay, well, that's the key question now. So we postulate that mutations in DNA repair can activate the part of the immune system that's also activated by viruses and bacterial infections, and this occurs in many auto inflammatory disorders. It's lupus. These pathways are activated when DNA repair is damaged and it activates the immune pathway that leads to to interferon production, which is an antiviral cytokine, and it leads to the activation of several other cytokines. We think that's happening and what we're doing now is we're studying cells with the PPOD mutation to see how it's affecting those immune pathways.

Dr. Herb Lachman:

How it's affecting those immune pathways and I think that our initial hypothesis might not hold true for PPOD. There are other parts of the cell that are damaged as a result of abnormal DNA repair, but the common theory is that abnormal DNA repair, either in the nucleus of the cell or in the mitochondria mitochondrial DNA, abnormal DNA repair will lead to the leakage of DNA from the nucleus and the mitochondria into the fabric of the cell, the cytosol, and that will act as if the cells are fooled into thinking that they're being exposed to a virus, so it'll activate that pathway. So if you already have that going on innately because of DNA repair problems and then you get hit with, let's say, sars-cov-2, which causes COVID-19, the combination of the two of them might trigger an inflammatory response. That's the hypothesis.

Susan Manfull, PhD:

Because it's sort of overloaded, if you will.

Dr. Herb Lachman:

Yeah, exactly yeah so you have the natural immune pathway activated by viruses, then you have this unnatural one, activated by, caused by abnormal DNA repair, and the two of them together might cause kind of an avalanche of activation, of the over-activation of the immune system.

Dr. Herb Lachman:

That's one possibility. It's much more complicated than that. I mean, this is just one idea and we're doing that in the lab now to try to find out whether those immune pathways are activated. But other things can happen in the cell as a result of abnormal DNA repair, Many but other things can happen in the cell as a result of abnormal DNA repair.

Dr. Herb Lachman:

Many, many other things can happen, which I mentioned in the second paper, thanks to Janet Cunningham, one of the co-authors, who pointed out that other things can happen when you have an abnormal repair of DNA.

Susan Manfull, PhD:

Do you want to talk about any of that?

Dr. Herb Lachman:

about what?

Susan Manfull, PhD:

Some of the other things that might happen.

Dr. Herb Lachman:

Oh yeah, yeah, so one of the things that can happen when DNA damage. First of all, DNA damage occurs all the time In everybody's cell. Every time a cell divides, every time we go out in the sun, every time we get exposed to an infection, DNA damage occurs and the DNA repair pathway fixes that DNA. It's not perfect. It's very good. If it wasn't very good, we'd all have cancer by the time we were 10. We have a very good way of about 100 genes that repair DNA. It's really an important process. We fix the DNA. When we can't fix it, the cells get damaged. They can get damaged and produce an overactive immune system. They get damaged and become senescent, meaning they can't divide anymore. They become damaged and cause mitochondrial dysfunction. And also they can cause a defect in the ability of genes to make proteins. The purpose of genes is that they code for proteins. The purpose of genes is to they code for proteins, so DNA damage can cause a problem in the ability of cells to produce proteins.

Dr. Herb Lachman:

DNA expression is the term and there are several other pathways also, and these are all possibilities and we're exploring all those phenomena in the context of PPM and DG. It's really challenging. It's a very, very hard set of experiments to do, really, really hard.

Susan Manfull, PhD:

So what are the implications in terms of treatment or prevention?

Dr. Herb Lachman:

Okay, that's a great question. That is the key question. I'm primarily a researcher, but I'm also an MD, very interested in patient care and translation, and right now the treatments for PANS are really suboptimal. Some kids respond to antibiotics, non-steroidal anti-inflammatories, ivig. Some kids could put on potent immune suppressors like Rituximab, and they may have a good response. They may not. What our studies are showing is, if it's true that the pathways that are being activated are the same immune pathways that are activated by viruses and certain bacteria and it's all leading to interferon dysregulation or dysregulation of several other cytokines, then it's possible that those cytokines can be targeted by some of the great medications that are being used now to treat autoimmune disorders.

Dr. Herb Lachman:

This is a very, very tough road that we're on for many, many reasons. One is that this disease occurs in kids and you can't just give these potent immune modulators to kids without having very, very solid evidence that it's going to do any good. And that's only going to happen when we go beyond the basic science stuff that I'm doing and actually do clinical studies uh, maybe even in animal models to show that these immune modulators can can interrupt an immune medimediated behavioral problem. It's a very, very long haul. No doctor is.

Dr. Herb Lachman:

One of the possibilities is an interferon inhibitor, for example, that's being used in lupus. It's a new treatment for lupus and people with lupus don't respond to more conventional treatment. Nobody is going to prescribe that potent interferon inhibitor to a kid without really really strong proof that it's going to do any kind of good. So the burden of proof is on us to show that these pathways are being activated, and then there'll be a burden to show that it works in animal models and clinical trials. I mean, we're talking about a very long haul and I wish I had an easy answer to the parents. I really don't. There's no easy answer. Some of the genes we're finding are saying you know something? Yes, this kid could respond to, let's say, an interferon inhibitor, or they could respond to another inhibitor of the immune system.

Dr. Herb Lachman:

There's so many different drugs monoclonal antibodies that are being developed. I feel my bones that some of these kids might respond, but we can't do it right now. It's not ethical because these kids they're kids and they're unproven medications and these are drugs that have really potentially dangerous side effects.

Susan Manfull, PhD:

So we're a ways away from finding some treatments, but it sounds like you're collecting data. That's promising.

Dr. Herb Lachman:

Well, which I think is very promising, and there are some doctors out there who are really really brave and parents who are very, very brave, and they're actually trying some of these medications, some of these immune modulators.

Dr. Herb Lachman:

I couldn't do it. Maybe that's why I'm on the bench and not with patients. I just can't do it. I'm a half-less-empty kind of person and I'm always't do it. I'm a half less empty kind of person and I'm always thinking about complications. You give this kid something and he or she is going to come down with a fatal fungal illness. That is my thought process. But then you have doctors who are much more aggressive and parents who are willing to try these treatments experimentally, and maybe the answer will come with them, as opposed to a very conservative therapeutic nihilist like me who really follows the do-no-harm rule of medicine.

Susan Manfull, PhD:

Well, I think so much depends on the severity of the disorder too, and how many other approaches they've tried that have not been successful.

Dr. Herb Lachman:

There will be some cases where the kids are really in bad shape, they haven't responded to IVIG, they haven't responded to rituximab, and then you say what do we do next? And that might be the next step and you might have kids there might be some kids who actually have an autoimmune, autoinflammatory disease that you would treat with these medications. That is a strong possibility.

Dr. Herb Lachman:

So they have the indication to try these medications like an interferon inhibitor because they have lupus or something else or severe inflammatory bowel disease and they have PANS too, and then you can study the physical disease and see what effect that has on the neuropsychiatric bubble.

Dr. Herb Lachman:

That, I think, is going to be the fastest route to showing that these things work. They're going to be tested in these kids for the inflammatory disorder and as a bystander we're going to study the effect it has on behavior. So to do this kind of work in a kid you need approval by the RV and you would not be able to get approval for these drugs to treat PANS or regression in autism, which is kind of the same family of PANS, neuroinflammatory disorder at the effect of these medications on refractory Crohn's disease, refractory lupus, and if the kid happens to have and that's how you get the IV approval and then you piggyback the observations you'd make on the effect it has on the neuropsychiatric problems. And this actually came out at the last conference, at the last Alex Manfull conference. We had this little get together and I you know I'm blocking his name, but he actually is trying to do that in you know he's piggybacking the neuroinflammatory problem on back, on the back of a somatic or systemic inflammatory disorder, which is a really brilliant strategy.

Susan Manfull, PhD:

So there is the research that Kyle is doing. There was a man in his 50s who had refractory OCD for years I mean 30 years, over 30 years, and he also had psoriasis.

Dr. Herb Lachman:

Yes, right.

Susan Manfull, PhD:

And he took Cosentix for the psoriasis and it was very successful. But it was also very successful in completely removing his OCD symptoms.

Dr. Herb Lachman:

Right. So that's another brilliant observation. And it turns out that the immune pathways that are overactive in psoriasis also are overactivated in the mouse model appendix. That's interleukin-17. And we're studying IL-17 and interleukin-17 in my lab, thanks to those pioneering studies. So yeah that kind of thing. Those are really really great studies and that is going to be the way we're going to crack into using these medications in kids who have refractory PANS. That'll happen much faster than doing studies on the PANS itself they're doing studies on the pants itself.

Susan Manfull, PhD:

So um there are other studies that show a connection to dna repair and and regression. Uh like down syndrome regression. Can you talk a little bit about that?

Dr. Herb Lachman:

yeah, so down syndrome regression is is the uh, I think it is the paradigm for an immune-mediated decompensation About 15%, that's 1.5%, of kids with Down syndrome. Adolescents with Down syndrome will have a severe regression. These kids are usually very social. Some of them have achieved a high level of independence and regression causes them to revert back to a much more underdeveloped state and they can develop psychiatric problems that they didn't have before. They have cognitive decline. That's down syndrome regression and there's evidence that this is immune-mediated because these kids do respond, or these adolescents do respond, to immune modulators like prednisone or IVIG. And a study came out a few months ago looking at genes that might separate those individuals with Down syndrome who regress from the other major population of people who don't regress. And Down syndrome is due to three copies of chromosome 21, which actually has some immune genes on it. But they found eight genes that were not linked to separate chromosomes. They found eight genes that had mutations that were associated with regression.

Dr. Herb Lachman:

And among those eight genes were four that affected same pathways. We predict to be affected without DNA repair genes. That's the interferon pathway.

Susan Manfull, PhD:

And three of those genes.

Dr. Herb Lachman:

Three of those four genes are DNA repair genes themselves.

Susan Manfull, PhD:

It's fascinating.

Dr. Herb Lachman:

So when I read that study I I you know I always have my doubts that I'm not. I've made so many mistakes in my life. Anytime I have a great discovery. Only a couple have really panned out. So most of the time I make I have a finding and it doesn't. It doesn't pan out. And when I saw that study I realized that I was on the right track. And one of the reasons why I'm still a little bit cautious is that most of these mutations that we have, that we found, are found in disease, but only when two copies of the gene are mutated.

Dr. Herb Lachman:

So, when two copies of ATM are mutated, it causes a disease called ataxia telangiectasia, which is very rare. Having one mutation does not cause that. So we have a burden of proof to show that having one mutation is enough to be a contributor to PANS or regression in autism. That's something that worries me. I have lots of theories to get around that.

Dr. Herb Lachman:

I really do and I think that's probably going to end up being right. But the bottom line is that unless when you have a end up being right. But the bottom line is that when a gene mutation is flagged as what we call autosomal recessive meaning you need two copies. A geneticist sees that and says this is meaningless, it's a parent carrier, they're not sick. And it turns out that if you have one copy of ATM, actually there's an increased risk of cancer. So having one copy actually can cause problems.

Dr. Herb Lachman:

What I'm seeing in my studies, when I dive deep into my analysis, when I feel the genes, what I'm finding is that I have genes, I have mutations that are likely pathogenic in five or 10 genes, in these kids, in these patients, and I'm thinking okay, so one, okay, one you can dismiss, maybe two you can dismiss, but maybe three or four or five interacting on the same pathway in the cell. The combination of having a small defect that by itself is meaningless, as opposed to having five or six of these that are individually meaningless but together they're coalescing to form to cause problems in the cell. That's my thinking right now.

Susan Manfull, PhD:

That makes sense.

Dr. Herb Lachman:

Yeah, you have to have a lot of mutations.

Susan Manfull, PhD:

Uh, and that's how I'm getting around this, this problem of explaining how a recessive disorder is causing a problem in a carrier so, herb, I think we probably have time for for one more question, and in our earlier talks you talked about some gut genes that you had identified. Can you talk a little bit about?

Dr. Herb Lachman:

yeah, okay so I mentioned earlier that the brain is the most complicated structure of the planet. The immune system is second and the gut is the third. And the connection between the planet.

Dr. Herb Lachman:

The immune system is second and the gut is the third and the connection between the gut and the brain, which I was very late to appreciate, is really something that is a real entity and there's this back and forth crosstalk between the brain and the gut and the gut actually has a ton of immune cells and the brain, through the vagus nerve, controls how the gut immune system functions and what I found I noticed a couple of patients had mutations in genes that are only expressed in the gut and I have one gene that I found. I found it in three cases and they're all pathogenic mutations and it's primarily expressed in the gut and it turns out those genes affect how the gut reacts to our load of bacteria that we have in our guts bacteria that we have in our guts In Crohn's disease, the breakdown in how we regulate the bacterial growth in our intestines. There's this incredible relationship between the gut microbiome and us. We have two pounds of bacteria in our guts. It's an amazing process, it's a co-evolutionary process.

Dr. Herb Lachman:

And how does the gut allow these microbes to exist? We need those microbes. We need them for digestion, we need them to produce vitamin K. They're part of the human system but every now and then there's a breakdown. The cells in the gut begin to recognize these bacteria as being enemies and it causes a breakdown of the gut mucosa and that leads to Crohn's disease. And some of the genes we're finding are actually Crohn's disease candidates and some of the families that I'm seeing with these other genes have a high prevalence of Crohn's disease, even though those genes themselves have not been found to be associated with Crohn's. So I have about five to 60 genes that are primarily expressed in the gut that I think might be causing neuroinflammation because of the breakdown in the gut-brain connection, a breakdown in the permeability of microbial products getting into the circulation and causing an immune response or inflammatory response. I really think that I'm on the right track there. Not published.

Susan Manfull, PhD:

And that's with PANS patients.

Dr. Herb Lachman:

Well, I'm combining PANS and regression in autism under the same general category. There's maybe no time to describe why I came to that conclusion, but these are patients both with PANS or regression.

Susan Manfull, PhD:

So we have Talk a little bit about that, please.

William Manfull:

Regression and PANS.

Dr. Herb Lachman:

Mm-hmm. So I don't see these patients clinically but I talk to the parents and I get the histories. Everything I know about the clinical aspects of PANS I get either from Jennifer Frankovich, renee Aker and families and my reading. I noticed that in some of the cases we had, you had one kid with PANS and the other kid was diagnosed with autism and seronegative autoimmune encephalitis or regression. They had a regressive episode following infections that did not meet PAN's criteria. They regressed in math, they regressed in cognitive function.

William Manfull:

They didn't have.

Dr. Herb Lachman:

OCD. Necessarily, they didn't have restricted eating, but they had other symptoms and they were in the same family.

William Manfull:

And when I analyzed their genes.

Dr. Herb Lachman:

Pardon me.

Susan Manfull, PhD:

Not as many um psychiatric symptoms.

Dr. Herb Lachman:

It sounds like oh plenty plenty but not, but they overlap, and most of them had anxiety, but they overlap. Uh, and kids with pans have have cognitive dysfunction too. Uh, it's just that the the clinical criteria for pans weren't met. They didn't have ocd or restricted eating. And they're in the same family. And some of these kids had one family of four kids that had pathogenic mutations in ATM. All four kids had that mutation plus others. Some of them had PANS, some of them had regression. And then it really dawned on me that this was that, this is that they're connected. This is they're connected and in Shang-3 mutations, the gene that causes autism. When these kids develop, when they become, when they regress, they either regress in cognitive function with some neuropsychiatric manifestations and some of them regress with a PANS-like clinical state. They have the PANS criteria, ocd and or restrictive eating plus the other symptoms. So I really look at it as all part of the spectrum of some immune-based decompensation that has fundamentally a similar genetic background.

Susan Manfull, PhD:

Well, do you think that we're going to find that there's a whole lot more overlap than we know right now in many of these disorders? I think so.

Dr. Herb Lachman:

I know that some autism doctors don't believe that you can have pans on top of autism. That's a nut to crack. If you have that belief system, then yeah, it's being undiagnosed. Actually, for those families that have kids with autism who regress, it's much better to communicate with the doctors from the point of view of these kids are having some acute regression, leaving pans out of the picture. They're regressing.

Dr. Herb Lachman:

And I have patients who have major, major regressions in my studies. They become catatonic, they become mute, they stop, they refuse to walk, they have cognitive decline. They really do resemble uh seronegative autoimmune syphilis and it's easy to approach uh these doctors who are pan skeptics from that point of view. My kid has autism and they are regressing so, herb, what are you working on?

Susan Manfull, PhD:

I know you're working on quite a few things, but what's captured your greatest attention right now?

Dr. Herb Lachman:

Well, like I said, the most fun I have is looking at these genes. So I'm doing two things. One of them is I'm doing my own sequencing at Einstein and looking at those genomes. I have very little funding to do this. This is really being done with very little funding. So we're doing that analysis. So I'm accumulating a whole list of genes that will hopefully come out in the next year in a series of papers New genes involved in DNA repair, these gut genes that I found, other genes involved in the immune system and mitochondrial genes.

Dr. Herb Lachman:

That's another thing that we haven't talked about, that we're finding mutations in genes that affect mitochondrial function. So we're working on the genetic part and then on the other side is doing what we call molecular studies. How do these genes affect the function of neurons and the brain's immune cells, which are microglia? So in the lab we're doing those studies. We're trying to see when you have these mutations, what is that doing to the cell? How is it affecting the ability of microglia to produce cytokines? How is it affecting neuronal function? So we're doing the genetic study to find the genes and we're doing the molecular studies to find out what those genes are doing to those cells.

Dr. Herb Lachman:

Wow, well, we look forward to to getting an update sometime soon yes, I think that we need science updates in this current anti-science climate, to say the least. This is why I retreat into science. The more I get exposed to the world, the more I retreat into science. The more I get exposed to the world, the more I retreat into science, which is beautiful. Scientists may not be beautiful, but science is very beautiful.

Susan Manfull, PhD:

Well, we hope you emerge to come to our brunch in DC in April to talk about it.

Dr. Herb Lachman:

I'll rearrange my schedule to be there.

Susan Manfull, PhD:

Excellent, because we'll be looking forward to seeing you All. Right, well, is there anything that you'd like to add that we didn't cover before we?

Dr. Herb Lachman:

I'm going to leave mitochondria for the next webinar.

Susan Manfull, PhD:

Excellent, and maybe microglia.

Dr. Herb Lachman:

Oh, yeah, yeah.

Susan Manfull, PhD:

All right. Thank you so very much.

Dr. Herb Lachman:

Well, thank you, we can't do this stuff without you. The parents are so important in this process I can't tell you how important it is and I really view us, I view my parents, the parents I deal with, as really great amateur scientists. Some of them know a lot and they send me papers and they challenge me and I say you know, I didn't know that, I didn't see that paper. They send me stuff. I learn from them. So we are a partnership. Now we need a third arm of that partnership, which is somebody with a billion dollars who can donate money for this research.

Dr. Herb Lachman:

We need a Michael J Fox.

Susan Manfull, PhD:

Yeah, we do, Herb. Thank you so very much. I look forward to seeing you and talking to you later.

William Manfull:

This concludes Episode 11 of Untangling Pandas in Pans. Thank you for listening. For more information about Pandas and Pans and the Alex Manful Fund, please visit thealexmanfulfundorg. The content in this podcast is not a substitute for professional medical advice, diagnosis or treatment. No-transcript.

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